In recent years, investigations into the biochemical pharmacology of ethanol have focussed on the role of tetrahydroisoquinoline (TIQ) alkaloids (which are condensation products of acetaldehyde, the primary metabolite of ethanol, with endogenous catecholamines) as possible mediators of the adrenergic, cardiovascular, and behavioral effects of ethanol. Both in vitro and acute in vivo studies have demonstrated the biosynthesis of these TIQs in animals and in man. Speculations on the role of TIQs in the development of physical dependence to ethanol have received significant attention, however no direct cause-effect relationship has been presented in support of this contention. This investigation will attempt to establish such a relationship, viz: (1) the demonstration of TIQ biosynthesis in vivo during ethanol or acetaldehyde dependence, and (2) inhibition of ethanol or acetaldehyde dependence by interfering with TIQ biosynthesis. Mice will be rendered physically dependent on ethanol or acetaldehyde by chronic inhalation exposure, and brain, blood, and adrenal levels of TIQs (epinephrine-TIQ, norepinephrine-TIQ, salsolinol, tetrahydropapaveroline) will be determined at the peak of physical dependence, at the time of withdrawal, and following recovery from withdrawal. In protection studies, mice will be protected with various agents which interfere with TIQ biosynthesis, prior to chronic exposure to ethanol or acetaldehyde. The degree of protection against physical dependence and withdrawal will be correlated with the degree of inhibition of TIQ biosynthesis. The results of these experiments should provide clues for a rational approach to the prevention or treatment of alcoholism.